Inflammatory carcinoma is the most aggressive variant of invasive mammary cancer in humans and dogs, being characterized by fulminant disease progression and a high mortality rate.1–3 Inflammatory carcinoma represents a distinct disease entity, rather than being part of the spectrum of advanced mammary tumors,1,3–5 and is associated with a high rate of early regional and distant metastases1 and a high incidence of locoregional recurrence if surgery is attempted.6 Accordingly, IC should be considered a systemic disease at the time of initial examination, even if metastases are not identified.7
A diagnosis of IC is made on the basis of clinical and histologic findings. Mammary IC is evident clinically as a rapidly enlarging mammary mass with concomitant signs of inflammation, such as erythema, induration of the mammary gland, warmth, signs of pain, and edema of the extremities. The condition can be mistaken for acute mastitis.2,3 Dermal lymphatic invasion by neoplastic cells is typically observed during histologic examination of affected tissues and represents a critical hallmark of the disease.3,5 Although IC does not refer to a specific histologic type, poorly differentiated or anaplastic carcinoma is usually diagnosed.3
In human medicine, evidence has accumulated to indicate that neoadjuvant systemic chemotherapy followed by mastectomy, radiotherapy, and possibly hormonal therapy offers the most favorable outcome.8 Current induction chemotherapy consists of administration of anthracyclines and taxanes.8 In veterinary medicine, dogs not euthanatized at the time of diagnosis have typically received only palliative medical treatment, such as antimicrobials, glucocorticoids, and NSAIDs, and the outcome of treatment has typically been poor. Identification of high tumor cyclooxygenase concentrations has opened up the possibility of treating IC with cyclooxygenase inhibitors,9 but no clinical follow-up data are currently available. Chemotherapy has been attempted only rarely, and surgical excision is often not an option because of extensive cutaneous involvement and concurrent coagulopathies.6 Regardless of the chosen treatment modality, overall survival time in most dogs with mammary IC does not exceed 30 days.2
Despite the reported unfavorable prognosis for dogs with mammary IC, results of treatment in a large cohort of affected dogs have not, to the authors' knowledge, been reported. The purposes of the study reported here, therefore, were to describe clinical characteristics, treatment, and outcome of dogs with mammary IC and identify patient-, tumor-, and treatment-related factors associated with overall survival time.
Materials and Methods
Criteria for selection of cases—Medical records of the authors' institutions were reviewed to identify female dogs with IC of the mammary gland examined between October 2003 and August 2008. Dogs were eligible for inclusion in the study if clinical signs and histologic findings were compatible with a diagnosis of mammary IC. A presumptive clinical diagnosis of mammary IC was made if a mammary mass was identified in conjunction with erythema, heat, and edema of the mammary gland. A histologic diagnosis of mammary IC was made if mammary carcinoma in conjunction with dermal lymphatic invasion was observed. Specimens for histologic examination were obtained by skin biopsy, including skin and dermis, or surgical excision.
Procedures—Information obtained from the medical records of dogs included in the study included signalment (ie, age, sex, body weight, and breed), history (ie, whether mammary tumors had been diagnosed previously and whether a mastectomy had been performed previously), tumor characteristics (ie, anatomic location within the mammary chain, size, and mobility), features of the overlying skin (ie, erythema, warmth, and presence of nodules or diffuse hardness), other physical examination findings (eg, edema of the extremities and inguinal or axillary lymphadenomegaly), whether coagulation abnormalities were identified, and clinical stage (determined on the basis of cytologic evaluation of regional lymph nodes, chest radiography, and abdominal ultrasonography).
For purposes of the present study, local metastasis was defined as neoplastic involvement of the regional lymph node, and distant metastasis was defined as neoplastic involvement of organs other than the mammary gland and regional lymph node. Cutaneous metastases were classified as distant metastases, as they were considered to represent hematologic or lymphatic spread of tumor cells. Dogs with mammary masses that had developed in previously normal mammary glands were classified as having primary IC, whereas dogs that had previously had mammary nodules were classified as having secondary IC.
When possible, information regarding the time elapsed between the owner's recognition of tumor-related clinical signs and the final diagnosis of IC was also gathered. For dogs with a history of mammary tumors, the time between appearance of the primary mammary tumor and the development of IC was recorded.
Information was retrieved on medical and surgical treatments provided to dogs included in the study. With regard to medical treatment, client preference determined whether dogs received particular drugs, including piroxicam and systemic chemotherapeutic agents. All dogs that received at least 1 dose of a drug were considered to have started treatment with the drug. Data were collected regarding all chemotherapeutic drugs used, dosage, number of doses administered, treatment-related adverse events, and response to treatment. Adverse events were classified according to standard criteria.10
Surgical excision was offered as a treatment option for dogs without any gross evidence of metastatic disease that did not have any coagulopathies and had localized mammary disease. The extent of surgery (monolateral vs bilateral mastectomy) was recorded.
Assessment of response to treatment—Response to treatment was assessed on the basis of physical examination findings and results of diagnostic imaging. For purposes of the present study, a complete response was defined as disappearance of IC, as determined by means of physical examination, and a lack of signs of systemic disease for at least 21 days. A partial response was defined as a > 50% decrease in the size of all measurable lesions, as determined by summing the products of the perpendicular dimensions of all measurable lesions, for at least 21 days and a lack of progression of preexisting lesions and lack of appearance of new lesions during that period. Stable disease was defined as no change or < 25% change in the size of measurable lesions for at least 21 days. Progressive disease was defined as a ≥ 25% increase in the size of measurable lesions or the appearance of new lesions or signs of dissemination. Responses lasting < 21 days were classified as progressive disease. For dogs undergoing surgical excision, the evaluated endpoint was time to progression.
Information on overall survival time and cause of death was obtained from the medical records. Survival time was calculated as the interval from histologic diagnosis to death attributable to IC.
Statistical analysis—The Kaplan-Meier product-limit method followed by the log-rank test was used to determine whether the following factors were significantly associated with survival time: age (< 10 years vs ≥ 10 years), sex (sexually intact female vs spayed female), body weight (< 20 kg [44 lb] vs ≥ 20 kg), IC classification (primary vs secondary), history of previous surgical excision of mammary tumors (yes vs no), anatomic site of the tumor (axillary, inguinal, or both), regional lymph node metastasis (present vs absent), distant metastasis (present vs absent), coagulopathy (present vs absent), and medical treatment (ie, administration of piroxicam, chemotherapeutic drugs, or both; yes vs no). Dogs were censored if they were still alive at the end of the data collection period or if they had died from a cause unrelated to IC.
The Kaplan-Meier method was also used to test for an association between survival time and the time from recognition of clinical signs to establishment of a diagnosis of IC and, for the subgroup of dogs with secondary IC, to test for an association between survival time and the time from the appearance of the primary tumor to development of IC. Factors for which the P value in the univariate analysis was < 0.15 were examined with the Cox proportional hazard model to evaluate their independence. All analyses were performed with standard software.a Values of P < 0.05 were considered significant.
Results
Patient and tumor characteristics—Forty-three dogs met the criteria for inclusion in the study. Mean age at the time of initial examination was 10.5 years (range, 6 to 15 years). There were 13 (30%) sexually intact females and 30 (70%) spayed females. Mean body weight was 25 kg (55 lb; range, 3.9 to 45 kg [8.6 to 99 lb]). There were 12 (28%) mixed-breed dogs, 10 (23%) German Shepherd Dogs, 3 (7%) Boxers, 2 (5%) Rottweilers, 2 (5%) Dalmatians, 2 (5%) English Setters, 2 (5%) Beagles, and 1 (2%) each of the following breeds: Belgian Shepherd Dog, Yorkshire Terrier, Pekingese, Maltese, Dogue de Bordeaux, Viszla, West Highland White Terrier, English Springer Spaniel, Labrador Retriever, and Doberman Pinscher.
Twenty-six of the 43 (60%) dogs had primary IC, whereas 17 (40%) dogs had secondary IC. In 15 of the 17 dogs with secondary IC, the condition developed at the same site where mastectomy had previously been performed because of noninflammatory mammary carcinoma. The remaining 2 dogs had not undergone mammary surgery previously, and IC developed in mammary glands that had tumors for 201 and 240 days. For all dogs, the diagnosis of IC was made for the first time at the time of initial examination at the authors' institutions. Mean time between the owner's recognition of the disorder and the definitive diagnosis of IC was 54 days (range, 3 to 209 days). For dogs with secondary IC, mean time between diagnosis of a noninfammatory carcinoma and IC was 181 days (range, 67 to 398 days).
Thirty of the 43 (70%) dogs had IC in the inguinal region, 10 (23%) had IC in the axillary region, and 3 (7%) had IC in both the inguinal and the axillary region. All dogs had clinically apparent IC at the time of initial examination. The most important findings during physical examination included erythema and warmth (all dogs), generalized induration of the involved mammary glands (all dogs), cutaneous nodules affecting the overlying skin (30 [70%]), regional lymphadenomegaly (27 [63%]), edema of the proximal portion of the hind limbs (25 [58%]), a palpable mammary mass (5 [12%]), and cutaneous lymphatic leakage leading to localized edema (2 [5%]). Clinically, 39 (91%) dogs appeared to be in pain, as evidenced by panting, abnormal posture, high heart rate, reacting before being touched, and vocalizing when touched. Additional clinical abnormalities reported by the owners included weakness (39 [91%]), poor appetite or anorexia (32 [74%]), and vomiting (5 [12%]).
Diagnostic staging tests were performed in each case on the day of initial examination. Cytologic assessment of regional lymph nodes revealed metastasis in 18 (42%) dogs, including metastasis to the axillary lymph nodes in 7, the inguinal lymph nodes in 8, and both the axillary and inguinal lymph nodes in 3. Results of thoracic radiography were normal in 31 (72%) dogs, whereas pulmonary metastases were detected in the remaining 12 dogs. Abdominal ultrasonography revealed metastasis to the sublumbar lymph nodes in 2 (5%) dogs and metastasis to the spleen in an additional 2 (5%) dogs. In these 4 dogs, metastatic disease was confirmed cytologically. Altogether, 35 of the 43 (81%) dogs had distant metastases at the time of initial examination, and an additional 2 dogs had local metastases. Six (14%) dogs did not have either local or distant metastases.
In 29 (67%) dogs, a panel of coagulation tests was performed in conjunction with the initial diagnostic testing, with all samples analyzed immediately. In 23 dogs, prothrombin time (reference range, 6.8 to 8.7 seconds) and activated partial thromboplastin time (reference range, 10.2 to 12.6 seconds) were within reference limits. Six (21%) dogs had prolonged prothrombin times (median, 13.1 seconds; range, 10.6 to 22.4 seconds) and activated partial thromboplastin times (median, 14.5 seconds; range, 13.7 to 35 seconds). Of the 6 dogs with abnormal coagulation testing results, 3 had local and distant metastases, 2 had only local metastases, and 1 did not have any metastases at the time of initial evaluation.
Neoplastic tissue for histologic confirmation of the diagnosis was obtained by means of punch biopsy in 40 (93%) dogs and by means of surgical excision in 3 (7%). The dominant pathological finding was high-grade ana-plastic carcinoma with infiltrating ductal features (43 [100%]); 5 (12%) dogs also had associated in situ ductal carcinoma. Dermal lymphatic invasion was identified in all dogs, whereas angiolymphatic invasion surrounding the tumor was observed in 27 (63%) dogs.
Treatment—Sixteen (37%) dogs did not receive any specific treatment for IC, 24 (56%) received medical treatment only, 2 (5%) underwent surgical excision and received medical treatment, and 1 (2%) underwent surgical excision only.
Of the 26 dogs that received medical treatment, 11 (42%) had distant metastases, 10 (38%) had local and distant metastases, 1 (4%) had local metastases, and 4 (15%) had no metastases at the time of pretreatment evaluation. Of the 17 dogs that did not receive medical treatment, 8 (47%) had distant metastases, 6 (35%) had local and distant metastases, 1 (6%) had local metastases, and 2 (12%) had no metastases at the time of pretreatment evaluation. As a whole, the 2 groups (dogs that received medical treatment vs those that did not) were considered equally matched with regard to disease status at the time of initial examination.
With regard to the 6 dogs with abnormal coagulation test results, 4 received medical treatment, and 2 did not receive any treatment.
Eighteen of the 26 (69%) dogs that received medical treatment were treated with piroxicam at a dosage of 0.3 mg/kg (0.14 mg/lb), PO, every 24 hours, whereas the remaining 8 received piroxicam and carboplatin (n = 4), piroxicam and doxorubicin (2), piroxicam and capecitabine (1), or piroxicam and cisplatin (1).
The 4 dogs that received carboplatin were treated at a dosage of 300 mg/m2, IV, every 21 days; mean number of doses was 3 (range, 1 to 5). Doxorubicin was administered once in 2 dogs at a dosage of 30 mg/m2, IV; in both dogs, treatment was subsequently stopped because of progressive disease. Capecitabine was administered to 1 dog at a dosage of 750 mg/m2, PO, every 24 hours for 7 days; an additional course was not given because a response was not achieved. Cisplatin was administered by means of intracavitary administration in 1 dog with pulmonary metastases; the dosage was 60 mg/m2.
Information on toxic effects was available for all dogs that were treated medically. Overall, medical treatment was well tolerated, with only 1 dog treated with piroxicam and 1 dog treated with piroxicam and doxo-rubicin developing grade 1 gastrointestinal tract toxicosis. None of the dogs developed evidence of bone marrow toxicosis.
For the 3 (7%) dogs that underwent surgical excision, surgery consisted of radical unilateral mastectomy. One dog was also treated with piroxicam, and a second dog received piroxicam and carboplatin. Histologic examination of excised tissues revealed residual neoplastic cells at the surgical margins in all 3 dogs.
Outcome and analysis of prognostic factors—Follow-up information was available for all 43 dogs. Overall, 41 (95%) dogs had progressive disease, and 2 (5%) had stable disease. For all 3 dogs that underwent surgery, time to tumor progression was < 14 days. Forty (93%) dogs were euthanatized because of progressive disease, whereas 3 (7%) dogs were still alive 30, 97, and 300 days after the diagnosis of IC.
Mean survival time for all 43 dogs was 60 days (range, 1 to 300 days). Survival times for the 3 dogs that underwent surgery were 40, 264, and 278 days.
Univariate analysis indicated that age, the presence of a coagulopathy, medical treatment, and time from recognition of clinical signs to establishment of a diagnosis of IC were potentially associated (ie, P < 0.15) with survival time (Table 1). However, the only factors significantly associated with survival time in the multivariate analysis were the presence of a coagulopathy and use of medical treatment. Dogs with a coagulopathy survived a significantly shorter time than did dogs without a coagulopathy (odds ratio, 0.28; 95% confidence interval, 0.10 to 0.80; P < 0.05; Figure 1), and dogs that received medical treatment survived significantly longer than dogs that did not (odds ratio, 2.54; 95% confidence interval, 1.27 to 5.08; P < 0.01; Figure 2).
Results of univariate, Kaplan-Meier analysis of factors potentially associated with survival time in dogs with IC.
| Factor and categories | No. of dogs | Mean survival time (d) | Hazard ratio | 95% CI | P value |
|---|---|---|---|---|---|
| Age | 0.60 | 0.27–1.11 | 0.09 | ||
| < 10 y | 30 | 96 | |||
| ≥ 10 y | 13 | 38 | |||
| Sex | 1.18 | 0.60–2.32 | 0.63 | ||
| Sexually intact female | 13 | 56 | |||
| Spayed female | 30 | 67 | |||
| Body weight | 1.10 | 0.54–2.25 | 0.79 | ||
| < 20 kg (< 44 lb) | 13 | 52 | |||
| ≥ 20 kg (≥ 44 lb) | 30 | 62 | |||
| IC classification | 1.24 | 0.66–2.40 | 0.49 | ||
| Primary | 26 | 53 | |||
| Secondary | 17 | 69 | |||
| Previous surgical excision | 1.02 | 0.52–1.98 | 0.96 | ||
| No | 28 | 58 | |||
| Yes | 15 | 59 | |||
| Anatomic site | NA | NA | 0.16 | ||
| Axillary | 10 | 28 | |||
| Inguinal | 30 | 57 | |||
| Both | 3 | 172 | |||
| Regional lymph node metastasis | 1.18 | 0.63–2.20 | 0.61 | ||
| Absent | 25 | 58 | |||
| Present | 18 | 61 | |||
| Distant metastasis | 1.03 | 0.46–2.31 | 0.93 | ||
| Absent | 8 | 58 | |||
| Present | 35 | 59 | |||
| Coagulopathy | 0.50 | 0.11–1.25 | 0.11 | ||
| Absent | 23 | 83 | |||
| Present | 6 | 23 | |||
| Medical treatment | 2.23 | 1.34–6.50 | 0.01 | ||
| No | 17 | 24 | |||
| Yes | 26 | 80 | |||
| Time from owner's recognition to final diagnosis (d) | NA | NA | 0.07 | ||
| 0 to 25 | 11 | 121 | |||
| 26 to 50 | 12 | 31 | |||
| 51 to 75 | 12 | 27 | |||
| > 75 | 8 | 39 | |||
| Time from primary tumor to IC (d)* | 0.87 | 0.28–2.55 | 0.77 | ||
| 0 to 150 | 9 | 80 | |||
| > 150 | 8 | 42 | |||
For those dogs with secondary IC.
CI = Confidence interval. NA = Not applicable.
Kaplan-Meier curves of survival time for dogs with mammary IC that did (n = 6; solid line) or did not (23; dashed line) have evidence of coagulopathy at the time of diagnosis.
Citation: Journal of the American Veterinary Medical Association 235, 8; 10.2460/javma.235.8.967
Kaplan-Meier curves of survival time for dogs with mammary IC that did (n = 6; solid line) or did not (23; dashed line) have evidence of coagulopathy at the time of diagnosis.
Citation: Journal of the American Veterinary Medical Association 235, 8; 10.2460/javma.235.8.967
Kaplan-Meier curves of survival time for dogs with mammary IC that did (n = 6; solid line) or did not (23; dashed line) have evidence of coagulopathy at the time of diagnosis.
Citation: Journal of the American Veterinary Medical Association 235, 8; 10.2460/javma.235.8.967
Kaplan-Meier curves of survival time for dogs with mammary IC that did (n = 24; solid line) or did not (16; dashed line) receive medical treatment (ie, administration of piroxicam, chemotherapeutic drugs, or both).
Citation: Journal of the American Veterinary Medical Association 235, 8; 10.2460/javma.235.8.967
Kaplan-Meier curves of survival time for dogs with mammary IC that did (n = 24; solid line) or did not (16; dashed line) receive medical treatment (ie, administration of piroxicam, chemotherapeutic drugs, or both).
Citation: Journal of the American Veterinary Medical Association 235, 8; 10.2460/javma.235.8.967
Kaplan-Meier curves of survival time for dogs with mammary IC that did (n = 24; solid line) or did not (16; dashed line) receive medical treatment (ie, administration of piroxicam, chemotherapeutic drugs, or both).
Citation: Journal of the American Veterinary Medical Association 235, 8; 10.2460/javma.235.8.967
Discussion
Previous studies1,6 have suggested that mammary IC is an aggressive malignancy, with a tendency to metastasize at an early stage. This agrees with the results of the present study, in that 37 of 43 (86%) dogs had metastases at the time of initial examination. The high incidence of metastatic disease in the present study may have been due in part to the long times between the owner's recognition of the disorder and the definitive diagnosis of IC. In many instances, dogs were initially thought to have mastitis and treated with antimicrobials, delaying recognition and treatment of the tumor.
Previous studies2,4 of IC in dogs have found that most affected dogs did not live > 30 days after the diagnosis was established. The treatment of mammary IC in dogs remains a challenge, and the short survival times indicate that new therapeutic strategies are needed.
The only factor previously identified as being associated with prognosis in dogs with mammary IC is IC classification, with dogs that have primary IC having a worse clinical outcome than that for dogs that have secondary IC.3 Secondary IC seems to be more common in women11 and dogs.3 In the present study, however, primary IC was more common, with 26 (60%) dogs having primary IC, and IC classification was not found to be significantly associated with survival time.
Use of medical treatment and the absence of a coagulopathy were the only factors significantly associated with longer survival times among dogs in the present study. Because mammary IC is generally considered a rapidly progressive disease in dogs, medical treatment is usually not attempted, and there is debate about the role of chemotherapy in the management of mammary carcinoma as a whole.12–14 In women with IC, use of multiagent chemotherapeutic protocols has been shown to improve outcome,8,15,16 and medical treatment (ie, administration of piroxicam, chemotherapeutic drugs, or both) showed some promise in prolonging survival times among dogs in the present study. Clinically important treatment-related toxicoses were not observed in the present study, but this may have been due to the fact that dogs died before the onset of adverse effects or that some drugs (ie, doxorubicin, capecitabine, and cisplatin) were used in only small numbers of dogs.
In human medicine, the combination of surgery and multiagent chemotherapy has emerged as an important treatment for women with breast IC,17–19 with improvements in local control translating into longer survival times. Although many veterinary oncologists have argued against mastectomy in dogs with mammary IC, it is unclear whether surgery may be beneficial. An intriguing finding in the present study was that the 2 dogs that underwent surgical excision followed by medical treatment were the second and third longest survivors of the entire group. Although our findings are preliminary, they suggest that selected dogs with mammary IC may be candidates for surgical excision, and we believe that surgical removal of the involved mammary chain should be considered for dogs with limited cutaneous involvement, an absence of pulmonary metastasis, and normal coagulation parameters. Because removal of all neoplastic cells is difficult in dogs with IC, chemotherapy should also be performed to control local disease and metastases. An important principle of adjuvant chemotherapy is the inverse relationship between number of neoplastic cells and response to che-motherapy.20 If tumor burden is low (ie, minimal residual disease), the residual tumor cells easily regain the cell cycle, have a high growth fraction, and show higher drug susceptibility.20 It is also possible that recruitment of leukocytes into the surgical site and subsequent immune activation triggered by tissue damage may have had immunoenhancing effects,21 thereby contributing to local tumor control.
The presence of a coagulopathy was associated with a grave prognosis in the present study. However, because of the retrospective nature of the study, results of a coagulation profle were not available for 15 dogs, limiting our ability to draw conclusions. Previous research22 has shown that in dogs with mammary carcinoma, hemostatic abnormalities were more frequently observed among dogs with distant metastases or IC, but the underlying mechanism has not been precisely elucidated. In the present study, 6 of 29 (21%) dogs had a coagulopathy.
Younger (< 10 years) age and a shorter time from recognition of clinical signs to establishment of a diagnosis of IC were associated with longer survival times in univariate analyses in the present study. These factors were not retained in the multivariate model, but the reasons for this were unclear. It is possible that the relatively small number of dogs may have limited the power of our analysis, leading to type 2 errors (ie, failure to detect significance). In addition, motivated owners who sought a veterinarian's intervention earlier may also have been more willing to pursue treatment, thereby contributing to longer survival times.
Limitations of the present study are those inherent to all retrospective case series. The choice of whether to initiate treatment was not randomized, but left to the discretion of the owners and attending veterinarians, and the dogs' clinical status may have played some role in selection of a particular treatment, including a particular chemotherapeutic agent, over another. It is also possible that dogs with worse clinical conditions were less likely to receive treatment. Further limitations include the low number of cases, particularly in certain groups (eg, dogs undergoing surgery), preventing full analysis of these data, and the fact that in many cases, owners were unwilling to treat their dogs on the basis of the notion that IC traditionally carries a poor prognosis.
In conclusion, findings of the present study con-firmed that mammary IC is an aggressive condition in dogs and suggested that a diagnosis should be formulated as early as possible to have the best chance of responding to treatment. Histologic confirmation of the diagnosis and determination of coagulation parameters were critical steps in staging of the disease. Randomized clinical trials should be carried out to investigate the role of chemotherapy, either alone or in conjunction with surgery. Identifcation of additional prognostic factors may help enhance selection of dogs most likely to benefit from treatment while sparing those for which the prognosis will be poor regardless of treatment.
ABBREVIATION
| IC | Inflammatory carcinoma |
SPSS, version 11.0, SPSS Inc, Chicago, Ill.
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